The candidate, Dr. Bryen A. Jordan holds a Ph.D. degree from the Dept of Pharmacology at the NYU School of medicine. He is currently a research assistant professor at the Dept of Biochemistry at NYU School of Medicine. The career goals of the candidate are to obtain sufficient skills and knowledge during the award period to become an independent researcher at a medical or academic institution. The scientific goal of the proposal is to better understand the role of the postsynaptic density (PSD) in synaptic function. The proposed aims of the K01 will allow the candidate to master skills in mass spectrometry/proteomics, imaging analysis and electrophysiology which will greatly enhance the ability of the candidate to do independent research. The candidate will also gain important experimental and theoretical knowledge in the fundamentals of neurobiology to pursue a career in neuroscience. Dr. Edward Ziff will advise and guide the candidate to become an independent scientist. Dr. Ziff has previously trained a number of highly successful researchers including Dr. Michael Greenberg and Dr. Thomas Kouzarides. Additionally, Dr. Moses Chao, Dr. Bernardo Rudy and Dr. Thomas Neubert wilf serve as co-mentors and provide general and specific guidance throughout the term of the proposal. NYU Medical Center and Dr. Edward Ziff provide a exemplary environment to conduct research for the candidate to obtain further training. A specialized cellular structure known as the PSD lies in direct apposition to active zones in most excitatory synapses. Assembled at the PSD are proteins that mediate and transmit presynaptic input, such as ionotropic glutamate receptors, scaffolding proteins and kinases and phosphatases. However recent proteomic studies demonstrate that the PSD is far more complex than previously thought. The long-term objective of this grant is to explore the molecular composition of PSDs and identify novel components that regulate synaptic function. Preliminary work has identified 452 proteins from PSDs purified from whole brains. This work has uncovered a novel set of proteins with nuclear localization signals that are highly enriched in PSDs. One of these can shuttle rapidly into the nucleus in response to NMDA receptor stimulation. Specific aims are to 1)- Identify region-specific differences in PSD composition by liquid chromatography and mass spectrometry of purified PSDs from hippocampus, striatum and cerebellum. 2)- To characterize the nuclear translocation of our identified targets in dissociated neurons and in slice cultures by chemical and electrical stimulation 3)- to explore the mechanisms and components of nuclear translocation in response to synaptic stimulation and to assess the function of these proteins in the nucleus. This project will provide an in-depth look at the complexity of the PSD and identify region specific factors. Furthermore, this project will analyze novel proteins that can shuttle to the nucleus in response to synaptic stimulation. This work will increase our understanding of synaptic function which is critical in learning and memory.